United States Patent [19J
`Gustafsson et al.
`
`[54] SUSTAINED RELEASE PARTICLES
`
`[75]
`
`Inventors: Nils-Ove Gustafsson, Liiddekiipinge;
`Timo Laakso, Hiillviken; Peter Fyhr,
`Bjarred; Monica Jonsson, Bara, all of
`Sweden
`
`[73] Assignee: Biogram AB, Malmo, Sweden
`
`[21] Appl. No.:
`
`09/051,709
`
`[22] PCT Filed:
`
`Sep. 3, 1996
`
`[86] PCT No.:
`
`PCT/SE96/01091
`
`§ 371 Date:
`
`Apr. 17, 1998
`
`§ 102( e) Date: Apr. 17, 1998
`
`[87] PCT Pub. No.: WO97/14408
`
`PCT Pub. Date: Apr. 24, 1997
`
`[30]
`
`Foreign Application Priority Data
`
`I 1111111111111111 11111 111111111111111 IIIII 1111111111 11111 111111111111111111
`US006120787 A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,120,787
`Sep.19,2000
`
`4,623,588
`4,637,905
`4,666,704
`4,677,191
`4,822,535
`4,835,139
`4,849,228
`5,275,819
`5,288,502
`5,417,982
`5,679,377
`
`11/1986 Nuwayser et al. .
`1/1987 Gardner .
`5 /1987 Shala ti et al. .
`6/1987 Tanaka et al. .
`4/1989 Ekman et al. .
`5 /1989 Tice et al. .
`7/1989 Yamamoto et al. .
`1/1994 Amer et al. .
`2/1994 Mc Ginity et al. ..................... 424/484
`5/1995 Modi .
`10/1997 Bernstein et al.
`
`...................... 424/491
`
`FOREIGN PATENT DOCUMENTS
`
`0535937 Al
`88/07870
`90/13780
`94/12158
`
`4/1993
`10/1988
`11/1990
`6/1994
`
`European Pat. Off ..
`WIPO.
`WIPO.
`WIPO.
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-William E. Benston, Jr.
`Attorney, Agent, or Firm-Burns, Doane, Swecker &
`Mathis, L.L.P.
`
`Oct. 19, 1995
`
`[SE]
`
`Sweden .................................. 9503672
`
`[57]
`
`ABSTRACT
`
`Int. Cl.7 ........................................................ A61F 2/00
`[51]
`[52] U.S. Cl. .......................... 424/426; 424/489; 424/497;
`424/486; 424/461; 424/468; 424/426; 424/490
`[58] Field of Search ..................................... 424/426, 489,
`424/490, 491, 488, 402.21, 484, 485, 486
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5/1983 Fong .
`4,384,975
`4,479,911 10/1984 Fong.
`2/1986 Nuwayser et al. .
`4,568,559
`
`A method of preparing parenterally administrable sustained
`release microparticles, which comprises preparing core par(cid:173)
`ticles in an aqueous medium that is essentially free from
`organic solvent, a biologically active substance being
`entrapped therein during or after said preparation, drying the
`core particles and coating the same with a release(cid:173)
`controlling polymer by air suspension technique so as to
`create a shell on the core particles without any detrimental
`exposure of the active substance to organic solvent. Micro(cid:173)
`particles obtainable by such a method also are provided.
`
`32 Claims, 5 Drawing Sheets
`
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`Days
`
`APOTEX EXHIBIT 1064
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`U.S. Patent
`
`Sep.19,2000
`
`Sheet 1 of 5
`
`6,120,787
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`

`

`U.S. Patent
`
`Sep.19,2000
`
`Sheet 2 of 5
`
`6,120,787
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`

`

`U.S. Patent
`
`Sep.19,2000
`
`Sheet 3 of 5
`
`6,120,787
`
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`

`

`U.S. Patent
`
`Sep.19,2000
`
`Sheet 4 of 5
`
`6,120,787
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`U.S. Patent
`
`Sep.19,2000
`
`Sheet 5 of 5
`
`6,120,787
`
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`
`

`

`6,120,787
`
`1
`SUSTAINED RELEASE PARTICLES
`
`This application is a 371 of PCT/SE96/01091 filed Sep.
`3, 1996.
`
`TECHNICAL FIELD
`The present invention is within the field of sustained
`release particles for parenteral administration of biologically
`active substances, especially drugs. More specifically it
`relates to a new preparation method for such particles 10
`containing a biologically active substance as well as to new
`sustained release particles obtainable thereby.
`
`BACKGROUND OF THE INVENTION
`Many drugs have to be administered by injection since
`they are either degraded or absorbed inefficiently when
`given for instance orally or nasally or by the rectal route. A
`drug formulation intended for parenteral use has to meet a
`number of requirements in order to be approved by the
`regulatory authorities for use in humans. Thus, it has to be
`biocompatible and biodegradable and all substances used
`and their degradation products should be non toxic. In
`addition thereto, particulate drugs intended for injection
`have to be small enough to pass through the injection needle,
`which preferably means that they should be smaller than 200
`µm. The drug should not be degraded to any large extent in
`the formulation during production or storage thereof or after
`administration and should be released in a biologically
`active form with reproducible kinetics.
`One class of polymers which fulfils the requirements as to
`biocompatibility and biodegradation to harmless end prod(cid:173)
`ucts are the linear polyesters based on lactic acid, glycolic
`acid and mixtures thereof. In the text below said polymers
`will also be referred to as PLGA. PLGA is degraded by ester
`hydrolysis to lactic acid and glycolic acid and has been 35
`shown to display excellent biocompatiblity. The innocous
`nature of PLGA is furthermore exemplified by the approval
`of several parenteral sustained release formulations based on
`these polymers by regulatory authorities, like the US Food
`and Drug Administration.
`Parenterally administrable sustained release products on
`the market today based on PLGA include Decapeptyl™
`(Ibsen Biotech), Prostap SRu (Lederle), Decapeptyl® Depot
`(Perring) och Zoladex® (Zeneca). The drugs of these for(cid:173)
`mulations are all peptides. In other words they consist of 45
`amino acids condensed to a polymer with a relatively low
`degree of polymerisation and they do not have any well
`defined three-dimensional structure. This in turn generally
`permits the use of rather harsh conditions during prepara(cid:173)
`tions of said products. For example extrusion and subse- 50
`quent size reduction can be used, which techniques should
`not be permissible in connection with proteins since they
`generally do not withstand such harsh conditions.
`Consequently there is also a need for sustained release
`formulations for proteins. Proteins are similar to peptides in 55
`that they also consist of amino acids, but the molecules are
`larger and most proteins are dependant on a well defined
`three-dimensional structure as to many of their properties,
`including biological activities and immunogenicity. Their
`three-dimensional structures can relatively easily be 60
`destroyed, for example by high temperatures, surface
`induced denaturation and, in many cases exposure to organic
`solvents. Thus, a very serious drawback in connection with
`the use of PLGA, which is an excellent material per se, for
`sustained release of proteins is the requirement to utilize 65
`organic solvents to dissolve said PLGA, with the associated
`risk of compromising the stability of the protein.
`
`2
`Despite large efforts aiming at a modification of the PLGA
`technology in order to avoid this inherent problem with
`protein instability during the preparation process the
`progress in this field has been very slow and as yet no protein
`5 products have appeared on the market based on PLGA
`technology. The main reason therefore probably is that the
`three-dimensional structures of most proteins are too sensi(cid:173)
`tive to withstand the preparation procedures used and/or
`being stored in a PLGA-matrix.
`The most commonly used technique at present for entrap(cid:173)
`ping water soluble substances such as proteins and peptides
`is the use of multiple emulsion systems. The drug substance
`is dissolved in a water or buffer solution and then mixed with
`an organic solvent, immiscible with water, containing the
`15 dissolved polymer. An emulsion is created having the water
`phase as the inner phase. Different types of emulsifiers and
`vigorous mixing are often used to create this first emulsion.
`Said emulsion is then transferred, under stirring, to another
`liquid, typically water, containing another polymer, for
`20 example polyvinylalalcohol, giving a triple w/o/w-emulsion.
`The microspheres are then hardened in some way. The most
`commonly used way is to utilize an organic solvent having
`a low boiling point, typically dichloromethane, and to
`evaporate the solvent. If the organic solvent is not fully
`25 immiscible with water, a continuous extraction procedure
`can be used by adding more water to the triple emulsion. A
`number of variations of this general procedure are also
`described in the literature. In some cases the primary emul(cid:173)
`sion is mixed with a non-aqueous phase, for instance silicon
`30 oil. Solid drug materials rather than dissolved drugs can also
`be used.
`The release profiles of proteins from microspheres pre(cid:173)
`pared by said method often show a fast initial release
`followed by a slower phase. Said slower phase can be
`followed by a third phase of faster release.
`PLGA microspheres containing proteins are disclosed in
`WO-Al-9013780, the main feature of which is the use of
`very low temperatures during the manufacture of the micro-
`40 spheres in order to retain high biological activity of the
`proteins. The activity-of encapsulated superoxide dismutase
`was measured but merely on the portion released from the
`particles. This method has been used to produce PLGA
`microspheres containing human growth hormone in
`WO-Al-9412158 by dispersing human growth hormone in
`methylene chloride containing PLGA, spraying the obtained
`dispersion into a container with frozen ethanol with a layer
`of liquid nitrogen thereabove in order to freeze the droplets
`and allow them to settle in the nitrogen on to the ethanol.
`The ethanol is then thawed and the microspheres start to sink
`in the ethanol where the methylene chloride is extracted into
`the ethanol and the microspheres are hardened. This
`approach may be able to retain the stability of proteins better
`than most other processes for entrapping proteins in PLGA
`microspheres. However, this still remains to be unequivo(cid:173)
`cally demonstrated for other proteins.
`However, in the earlier mentioned methods based on
`encapsulation with PLGA the active substances are sub(cid:173)
`jected to an organic solvent and this is generally detrimental
`to the stability of a protein. In addition thereto, the emulsion
`processes referred to above are complicated and likely to be
`problematic to scale up to an industrial scale. Furthermore,
`many of the organic solvents used in many of these pro(cid:173)
`cesses are fraught with environmental problems and their
`high affinities for the PLGA polymer make removal difficult.
`A parenterally administrable sustained release formula(cid:173)
`tion should be able to control the release of the entrapped
`
`

`

`6,120,787
`
`3
`drug in an accurate way. In many of the systems based on
`PLGA the release of the active ingredient is largely depen(cid:173)
`dent on the amount of drug substance incorporated into the
`microparticle, due to the formation of channels in the
`microparticles at higher drug loadings. This also contributes
`to a high initial burst at high drug loading.
`A well known way of controlling the release of small
`molecules from a solid core is to apply a coating that
`produces a rate controlling film on the surface of the core.
`This is a general method of controlling the release rate of
`drugs to be administered by the oral route. One way of
`applying similar coats is by the use of air suspension
`technology. However, in connection with coating particles
`for use in parenteral administration, which particles are
`generally of a size below 200 µm, and often smaller,
`generally severe problems are encountered. Such problems
`can be an increased tendency for particles to agglomerate
`and problems with static electricity disturbing the manufac(cid:173)
`turing process.
`Some different ways of coating particles of such small
`sizes are dispersion of the drug in a solution of the coating
`material and subsequent spray drying and a number of
`coacervation methods where a dissolved polymer is used to
`encapsulate the core material in different ways. However, all
`these methods would expose a protein to the organic solvent
`used to dissolve the PLGA. A method where a fluidized bed
`is used in the coating of microparticles is disclosed in U.S.
`Pat. No. 4,568,559. Here a solid, dry composite admixture is
`prepared from a uniform dispersion of an active ingredient
`of a film-forming polymer, the admixture then being ground
`and the resulting particles being sieved to obtain a size
`distribution of 1-150 µm. The core particles are then coated
`in a fluidized bed, a prerequisite, however, being that the
`same, or substantially the same, film-forming polymer mate(cid:173)
`rial is used both for the preparation of the composite core
`and the coating to provide for bonding of the wall coating of
`the film-forming polymer to the core material. Thus, this
`method does not either eliminate the problem of exposing
`the protein to organic solvents if the film-forming polymer
`is PLGA or any other polymer that is not water soluble.
`Thus, a method of producing parenterally administrable
`sustained release formulations for sensitive substances, for
`instance proteins, with the following properties would be
`highly desirable:
`that can control the release rate of the entrapped sub(cid:173)
`stances within wide margins, typically from one or a
`few days to at least around one month;
`that enables the production to be carried out with standard
`pharmaceutical equipment and which can be used from
`small scale manufacture to full scale production;
`that makes it possible to eliminate, or minimise, the
`exposure of the active ingredient to organic solvents;
`and
`that is completely biodegradable and has a surface of a 55
`biocompatible material.
`
`DESCRIPTION OF THE INVENTION
`According to the present invention it has been found
`possible to prepare a parenterally administrable sustained 60
`release formulation with the characteristics referred to
`above. The new method claimed thus makes it possible to
`take advantage of the excellent biocompatibility and release
`controlling properties of PLGA while avoiding or minimis(cid:173)
`ing the exposure of for instance a protein to be formulated
`to organic solvents. However, the invention is not restricted
`to the use of PLGA only as a coating material or the use of
`
`4
`a protein only as the active ingredient. Rather the invention
`is applicable to the use of any polymer that is film-forming,
`biodegradable and release-controlling, especially a polymer
`for which organic solvents have hitherto been utilized.
`5 Another prerequisite for a polymer is of course that it is
`pharmaceutically acceptable, which requirement is appli(cid:173)
`cable also to all other materials or ingredients used in the
`formulation. Furthermore, the invention is useful for all
`active substances which may be utilized in parenteral admin-
`10 istration. Primarily, however, the invention presents a solu(cid:173)
`tion to the previously described problem with active sub(cid:173)
`stances sensitive to or instable in organic solvents.
`Briefly the invention is based on the idea on entrapping
`the active ingredient in microparticles without using any
`15 organic solvent, working up the microparticles to the dry
`state and subsequently coating the microparticles with a
`biodegradable polymer using an air suspension technique to
`remove, very rapidly, any organic solvent used for the
`polymer coating to avoid any substantial exposure of the
`20 active substance to organic solvent.
`More specifically, according to a first aspect of the
`invention, a method is provided of preparing parenterally,
`preferably injectionally, administrable, sustained release
`microparticles containing a biologically active substance,
`25 especially a substance that is instable in the presence of an
`organic solvent, said method comprising preparing core
`particles from a biodegradable material in an aqeous
`medium that is essentially free from organic solvent, the
`biologically active substance being entrapped therein during
`30 or after said preparation, drying the core particles containing
`said active substance, optionally after a washing step to
`remove any excess of active substance, and coating the core
`particles with a film-forming, biodegradable, release(cid:173)
`controlling polymer by air suspension technique so as to
`35 create a shell of said polymer on the core particles without
`any detrimental exposure of the active substance to organic
`solvent.
`Since the method is primarily intended for the preparation
`of microparticles adapted for administration by injection, the
`40 microparticles preferably have an average diameter in the
`range of 10-200 µm. more preferably 20-100 µm. and most
`preferably smaller than 60 µm, e.g. 10-60 µm or 40-60 µm.
`A preferable core particle material is a starch or a chemi-
`45 cally or physically modified starch. Such materials are
`previously known per se in this technical field, and therefore
`reference can be made to the prior art concerning details
`about such starches. It can, however, be added that micro(cid:173)
`particles prepared from starch can be designed so as to be
`50 dissolved by a-amylase, an enzyme present in serum and
`extracellular fluid, and as the end degradation product is
`glucose, starch microparticles can fulfil the requirement of
`biodegradability.
`The preferred polymers for the shell are alifatic polyesters
`(e.g. homopolymers) or copolymers from (a-hydroxy acids
`or cyclic dimers of a-hydroxy acids.
`Said a-hydroxy acid is preferably selected from the group
`consisting of lactic acid and glycolic acid. In other words a
`preferred homopolymer can be for instance polylactic acid
`or polyglycolic acid, while a preferred copolymer can be a
`lactic acid/glycolic acid copolymer.
`The cyclic dimers are preferably selected from the group
`consisting of glycolides and lactides.
`However, as indicated above, other biodegradable poly-
`65 mers could also be used provided the polymer is able to form
`a film with the desired properties as to mechanical stability
`and release controlling properties, such as permeability to
`
`

`

`6,120,787
`
`5
`the active ingredient or the formation of pores. These
`properties could be fulfilled by the polymer itself or by
`including other substances in the coating. The coating mate(cid:173)
`rial used could of course also be a mixture of two or more
`of the polymers referred to. Furthermore, said polymers may 5
`also be used in the form of their salts.
`The biologically active substance can be entrapped in the
`microparticles without any use of organic solvent in several
`ways. An especially preferred way is the use of a so called
`aqueous two phase system technique, which is previously 10
`known per se. Said method is for instance disclosed in U.S.
`Pat. No. 4,822,535, which means that details about said
`technique can be found therein. Another way involves the
`preparation of core microparticles which are able to absorb
`water in a separate process, removal of any organic solvent
`used and loading the obtained microparticles with the active
`substance by exposing the dry microparticles to a solution of
`said active substance to have the solution absorbed by the
`microparticles, which are subsequently dried.
`The drying of the core particles can be accomplished by
`any appropriate means, for example by spray drying, freeze
`drying or vacuum drying. In order to remove excess of
`active substance the microparticles or cores could also be
`washed prior to the drying step.
`The core particles containing the active substance are
`subsequently coated by an air suspension technique which
`enables the creation of a shell of the polymer on the core
`particles without any substantial or detrimental exposure of
`the active substance to organic solvent. Said air suspension
`technique can be any method that is classified as an air
`suspension method and is able to apply a satisfactory
`coating. Preferred examples of such methods are methods
`wherein a fluidized bed or a so called spouted bed are
`utilized or the so called Wurster process, which method are
`all previously known per se and need not be described in
`detail here. Thus, the term "air suspension method" as used
`herein means any method where solid particles are sus(cid:173)
`pended in an upwardly moving stream of gas. Said gas could
`be any gas capable of evaporating the solvent used and need
`not necessarily be air in spite of the term "air" suspension.
`However, in connection with the air suspension technique
`it has been found that the problems with sensitive active
`substances and their exposures to organic solvents are
`eliminated, or essentially reduced, while preferably using a 45
`high flow rate of the air, or gas, sufficient to accomplish the
`desired result.
`According to a preferable embodiment of the method
`claimed the polymer is applied on to the core particles from
`a solution, a pseudolatex or an emulsion thereof. In this 50
`connection it should be noted that an organic solvent can be
`utilized as the solvent for the polymer, as it has unexpectedly
`been found that by the new method according to the inven(cid:173)
`tion the active substance is not influenced to any substantial
`extent by the presence of such a solvent.
`However, another preferable embodiment of the invention
`is represented by the case where said coating solution
`contains water, said pseudolatex is a pseudolatex of the
`polymer in water and said emulsion is an emulsion where
`one of the phases is a water phase. In the case of a mixture 60
`of different polymers, they can be present in different phases
`of an emulsion. Thus, it has been found that the presence of
`water can eliminate, or substantially reduce, the build up of
`static electricity during the coating procedure, and an espe(cid:173)
`cially preferred embodiment in this respect is the use of an 65
`emulsion where one of the phases is a liquid of the polymer
`in a solvent for said polymer and the other phase is water.
`
`6
`Last-mentioned emulsion is furthermore useful in a more
`general aspect, as will be described more specifically below
`and which also represents another aspect of the invention.
`Another preferable embodiment of the invention is rep(cid:173)
`resented by the case wherein one or more stabilizing agents
`are incorporated in the particles during the preparation
`thereof. The nature of such a stabilizing agent is of course
`dependent on the specific active substance to be stabilized
`and said agent is chosen in line with known principles.
`Additives can also be incorporated into the release-
`controlling polymer shell during the application thereof.
`Preferable examples of such additives are :film property
`modifying agents and release controlling agents. Examples
`as to the first category are plasticizers, e.g. triethyl-citrate,
`15 triacetin, polyethyleneglycol, polyethyleneoxide etc, while
`release controlling agents can be for instance inorganic
`bases (e.g. sodium hydroxide, potassium hydroxide, sodium
`carbonate, potassium carbonate, etc), organic bases (e.g.
`ethanol amine, diethanole amine, triethanole amine,
`20 lidocaine, tetracaine, etc,), inorganic acids (e.g.
`ammoniumsulfate, ammonium chloride, etc), organic acids
`(e.g. citric acid, lactic acid, glycolic acid, ascorbic acid, etc),
`and solid soluble substances which upon release create pores
`in the coating (e.g. crystals of sodium chloride, glucose,
`25 mannitol, sucrose, etc).
`Additives to be included in the case where an emulsion or
`a pseudolatex is created are for instance emulsifiers.
`The required amount of coating material depends on for
`example the size of the microcapsules, the composition of
`the coating and the desired release characteristics. Typical
`amounts are, however, 1-200 percent by weight, preferably
`5-100 percent by weight, based on the weight of the core.
`After the application of the coating controlling the release
`of the entrapped active substance additional materials could
`also be applied, e.g. sprayed, on to the microparticles in
`order to further modify the properties thereof or to facilitate
`the handling thereof. Examples of such materials are
`mannitol, sucrose and sodium chloride.
`As already indicated above the invention is especially
`interesting in connection with proteins, peptides and
`polypeptides or other drugs or biologically active substances
`which are sensitive to or instable in the presence of organic
`solvents. However, generally the invention is not limited to
`the presence of such substances only as the inventive idea is
`applicable to any biologically active substance which can be
`used for parenteral administration. Thus, in addition to
`sensitive or instability problems the invention may well be
`of special interest in cases where it would otherwise be
`difficult to remove solvents or where toxicological or other
`environmental problems might occur.
`According to a second aspect of the invention there is also
`provided parenterally administrable sustained release micro(cid:173)
`particles per se, which comprise a) core particles of a
`55 biodegradable material with the active substance entrapped
`therein, which core particles have been prepared in an
`aqueous medium essentially free from organic solvent, and
`b) a shell of a film-forming, biodegradable, release-
`controlling polymer on said core particles, which shell has
`been applied on said core particles by air suspension tech(cid:173)
`nique.
`As to preferable embodiments and examples of materials
`and techniques to be used in connection therewith, reference
`is made to all embodiments and examples specified above
`and which will not be repeated once more.
`According to a third aspect of the invention there is also
`provided a method of coating small particles in general,
`
`30
`
`35
`
`40
`
`

`

`7
`preferably microparticles as defined above, by air suspen(cid:173)
`sion technique, which method comprises applying on said
`particles, by air suspension technique, a coating emulsion of
`a coating material where one of the phases is a liquid of the
`coating material in a solvent and the other phase is water.
`Thus, by such a method it has been found possible to
`eliminate or reduce problems associated with static electric(cid:173)
`ity in air suspension coating of small particles.
`The background of this aspect of the invention is as
`follows. The technology of air suspension coating of tablets, 10
`granules and small particles is well known. When the
`coating is made with the coating material in an organic
`solvent static electricity can be a problem. This problem is
`more pronounced when coating small particles. Thus, small
`particles have a tendency of adhearing to the walls of the 15
`coating chamber and also to each other, making the problem
`with unwanted agglomeration more severe. Particles stick(cid:173)
`ing to the wall of the coating apparatus can cause uneven
`coating in the batch, lower yield and a less controllable
`process.
`For some coating polymers the use of an aqueous diser(cid:173)
`sion of latex or pseudolatex eliminates or reduces the
`problems associated with static electricity. It has not been
`possible to use a latex dispersion for all coating polymers 25
`with the same quality of the film being obtained from
`organic solvent based system. This aspect of the invention
`makes it possible to circumvent this problem.
`In this context it should be added that the particles in
`connection with the invention are not specifically limited as 30
`to size or composition. Thus, it may be a drug substance or
`particles containing drug substances, fertilizers, etc.
`The coating material is any coating material, e.g. a
`film-forming polymer, which could be used in air suspension
`coating and which is soluble in a solvent not totally miscible 35
`with water. Examples of coating materials are the polymers
`specifically referred to above. Examples of appropriate
`solvents are higher alcohols, esters, ethers, ketones, chlori(cid:173)
`nated hydrocarbons, aliphatic hydrocarbons and aromatic
`hydrocarbons.
`The coating emulsion is made by mixing an aqueous
`phase with an organic phase. The coating material is dis(cid:173)
`solved in the organic phase. The emulsification step can be
`carried out by any of the conventional dispersing
`procedures, such as intermittent agitation, mixing with a 45
`propeller, turbine mixer or magnetic mixer, colloid mill
`process, homogenisation process or sonification process.
`The organic phase can be either the internal or the external
`phase.
`An emulsifier may be added to stabilise the emulsion. 50
`Preferable examples thereof are anionic surfactants or non(cid:173)
`ionic surfactants. These emulsifiers can be used alone or in
`combination.
`The coating equipment used according to this aspect of 55
`the invention, as well as in connection with the first aspect
`of the invention, could be any type of air suspension
`equipment capable of coating particles, especially small
`particles.
`
`40
`
`EXAMPLES
`
`60
`
`The invention will now be exemplified by the following
`non-limiting examples wherein microparticles containing
`BSA, which is the most extensively used model protein for
`systems like this due to its well known characteristics and 65
`moderate cost, are coated with a layer comprising poly
`(lactide-co-glycolide ). Furthermore, microparticles contain-
`
`6,120,787
`
`8
`ing human insulin are coated, since insulin is known to be
`a sensitive protein and the biological activity of the final
`preparation can easily by assayed in vivo. The micropar(cid:173)
`ticles are prepared for example in accordance with technique
`5 disclosed in U.S. Pat. No. 4, 822,535. The coating is applied
`with commersially available equipment and the parameters
`set in the examples should merely be regarded as guidelines,
`since adjustments may be needed in many cases in order to
`obtain optimal conditions for the coating.
`Procedure for Preparing the Core Particles
`Example 1
`Two-phase immobilisation in accordance with U.S. Pat.
`No. 4,822,535.
`1. Weigh out 80 g of starch (Amioca 50, National Starch)
`and suspend in 320 g of 50 mM sodium bicarbonate buffer
`pH 9,8.
`2. Heat the suspension until the starch has been totally
`dissolved.
`3. Cool the solution to 50° C.
`4.Add 96 ml of a 9,26% BSA solution (room temperature)
`in 50 mM sodium bicarbonate buffer pH 9,8 and stir for
`10 seconds.
`5. Add starch-protein solution to 800 ml of a 20 w/w %
`polyethylene glycol solution in 50 mM sodium bicar(cid:173)
`bonate buffer pH 9,8 (room temperature, Av. Mol. Wt.
`20000), under continous stirring.
`6. After 2 minutes,. add 3200 ml of a 40 w/w % poly(cid:173)
`ethylene glycol solution in 50 mM sodium bicarbonate
`buffer pH 9,8 (room temperature, Av. Mol. Wt. 20000),
`under continous stirring.
`7. Stir for 24 h.
`8. The obtained microparticles are washed and vaccum
`dried.
`9. The dry microparticles are sieved through a 160 µm
`mesh.
`
`20
`
`Example 2
`
`1. Weigh out 80 g of starch (Amioca 50, National Starch)
`and suspend in 420 g of water.
`2. Heat the suspension until the starch has been totally
`dissolved.
`3. Cool the solution to 50° C.
`4. Add the starch solution to 800 ml of a 20 w/w %
`polyethylene glycol solution in water (room
`temperature, Av. Mol. Wt. 20000 D), under continous
`stirring.
`5. After 2 minutes, add 3200 ml of a 40 w/w % po